1. Field of the Invention
The present invention relates generally to the fields of biological psychiatry and neuropharmacology. More specifically, the present invention relates to a novel method of treating dysfunctional dopaminergic and nitric oxide related activity and related psychiatric and neurologic diseases.
2. Description of the Related Art
A wide variety of psychiatric and neurologic pathophysiologic states are believed to involve dysfunction of brain neurotransmitter and neuropeptide systems. A monoaminergic neurotransmitter that has drawn considerable attention over the last generation is dopamine. Anti-dopaminergic drugs, such as the neuroleptics haloperidol and chlorpromazine, have been the drugs of choice for various psychiatric and neurologic diseases such as schizophrenia. Despite moderate success, the antipsychotic dopamine antagonists have serious medical drawbacks including the gradual induction of permanent dyskinesias and a failure to counteract abnormal cholinergic interactions with dopamine. Thus, safer and more efficacious means of treating diseases such as schizophrenia are highly desirable.
A salient animal model has recently been developed for certain aspects of schizophrenic behavior and brain pathology. This animal model involves prenatal exposure to d-amphetamine in the rat in which there are early juvenile signs of behavioral changes suggestive of hypodopaminergia, followed by an increasing sensitivity to ultradian rhythm changes in striatal dopamine activity. As the offspring approach adulthood, there are significant increases in bodily activity, suggesting increased dopamine activity in the postpubertal period. There are also gradual increases in switching between alternative response possibilities, poorer reversal learning and finally increased perseveration in simple response, all of which have been characterized not only as functions of dopamine overstimulation in animals and humans but also as significant symptoms in schizophrenic patients.
In parallel, this animal model also shows changes in neuronal number in three brain regions similar to reported changes found in schizophrenia. Neuronal losses in the mediodorsal thalamic nucleus and in the nucleus accumbens both in schizophrenia and in animals exposed to prenatal d-amphetamine have been described. In contrast, there are increased numbers of nitric oxide synthetase (NOS)-containing cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei (PPTg/LDTg) in this animal model just as there are in schizophrenia. These cholinergic neurons can release nitric oxide and also directly affect the dopaminergic activity in the brain via the nigrostriatal pathway
The prior art is deficient in the lack of effective means of treating dopamine and nitric oxide dysfunctional states, in disorders such as schizophrenia in a manner that include treatment of the effect produced by these cholinergic, nitric oxide synthetase containing neurons. The present invention fulfills this need and desire in the art.